With the development in semiconductor micromachining techniques, it has become possible to perform machining in nanometer (nm) scale. Utilizing such techniques, a technology for analyzing nano-scale biomolecules such as DNA (Deoxyribo Nucleic Acid) molecules carrying genetic information has been developed.
FIG. 58 is a diagram showing a structural example of DNA molecule. A DNA molecule is formed by four types of bases (adenine (A), thymine (T), guanine (G), cytosine (C)) coupled to a polynucleotide chain.
FIG. 59 is a diagram showing a helical structure of a DNA molecule. As shown in FIG. 59 (a), it is known that a DNA molecule has a double helix structure comprising two chains. A and T, G and C respectively form pairs and are coupled by hydrogen bonding in the bases of each chain. When the double helix structure is formed, these pairs of bases are aligned with a spacing of about 0.34 nm from the polynucleotide chain. When the two chains are uncoupled to be single chains, the bases are aligned with a spacing of about 0.7 nm.
Namely, semiconductor micromachining techniques reach the technical level of machining nanostructures as small as inner structures of DNA molecules, which is an example of biomolecules. Therefore, it is possible to investigate characteristics of biomolecules according to electrical or mechanical characteristics of semiconductors.
FIG. 59 (b) is a diagram showing a single chain extracted from FIG. 59 (a). FIG. 59 (c) is a schematic diagram showing the single chain in which the helical structure is unbound. In this description, a single chain is shown as FIG. 59 (d) (e) (f) in some cases.
Because of aged society, there is a social need for detailed health managements or health cares on the basis of personal genetic information. Thus a technology has been developed for cost-effectively and rapidly analyzing personal genetic information using semiconductor micromachining techniques and semiconductor techniques. Since effects of medicines or management processes of health conditions are dependent on personal genetic information, the development is intended to promote medical care according to personal characteristics by analyzing personal genetic information.
FIGS. 60 and 61 are diagrams showing configuration examples of a DNA analysis apparatus. This apparatus: leads, for example, a single chain DNA or RNA (Ribo Nucleic Acid) to a small gap or a through hole formed by semiconductor micromachining technique; measures electric currents flowing through an electrode attached to the gap or the through hole; and analyzes structures or characteristics of DNA or RNA using the measurement results thereof. Hereinafter, the small gap or the through hole through which DNA or RNA passes is referred to as nanomolecule path. Other than DNA or RNA, general bio polymers such as enzyme or certain types of bacteria could be targets of the apparatus.
FIG. 60 is a diagram showing a configuration example of a DNA analysis apparatus in which DNAs pass via through holes (nanopores) formed by semiconductor micromachining technique. FIG. 60 (a) is a plain view, FIG. 60 (b) is a A-A′ sectional view of FIG. 60 (a), and FIG. 60 (c) is a B-B′ sectional view of FIG. 60 (a).
In FIG. 60 (a), the nanomolecule path is formed as a hole in which a part of Si plane is, for example, penetrated to the back surface. If the nanomolecule path is of circular shape, the diameter of the hole is about 1.5 nm to 3 nm. As shown in FIG. 60 (b), electrodes T1 and T2 are sandwiching the nanomolecule path and are sandwiched by thin film S1 and S2. As shown in FIG. 60 (c), portions other than the electrodes T1 and T2 are filled with a thin film S0. The S0, S1, and S2 are, for example, formed by silicon or silicon oxide or silicon nitride. The electrodes T1 and T2 are formed by titanium nitride or gold.
FIG. 61 is a diagram showing a configuration example of a DNA analysis apparatus in which DNAs pass through a small gap (nanogap) formed by semiconductor micromachining technique between the electrodes T1 and T2. FIG. 61 (a) is a plain view and FIG. 61 (b) is a A-A′ sectional view of FIG. 61 (a). As shown in FIG. 61 (a), the electrodes T1 and T2 sandwiched by the thin film S1 and S2 form a nanomolecule path as the small gap on the thin film S0 which works as the lower surface of the path.
Patent Literature 1 listed below discloses an apparatus in which a microgap is provided between two electrodes having a structure similar to FIG. 61, and the apparatus reads tunnel electrical currents that flow when DNAs pass through the gap. In Patent Literature 1, two electrodes are set up in two directions perpendicular to two electrodes facing to each other so that bases of DNA pass through at a desired speed, and voltages are applied to the electrodes to generate electric fields. The electric field may control the speed at which the bases of DNA pass through the gap.
Patent Literature 2 listed below discloses an apparatus in which DNAs pass through a microhole having a structure similar to FIG. 60. In Patent Literature 2, the microhole itself does not have electrodes and electrodes are set up above and below the microhole. Electric currents flowing through the electrodes are different depending on types of four bases included in DNA. Therefore, it is possible to identify types of bases passing through the microhole by comparing the electric current with table data prepared in advance.
FIG. 62 is a diagram showing an example of electric current flowing to two electrodes having a microgap or to two electrodes facing toward an opening direction of a microhole. FIG. 62 schematically shows FIG. 3 of Non Patent Literature 1 listed below. The vertical axis indicates amount of electric current flowing between the two electrodes and the vertical axis indicates occurrence frequency of the electric current for each measurement.
As shown in FIG. 62, the electric current flowing through the two electrodes distributes with respect to the measurement. In addition, large portions of the four bases overlap with each other. All distributions of the four bases spread across more than 5 digits. The distribution is caused because of the positional relationship between the base molecules and the electrodes, the relationship between the direction of the base molecules and the electrodes, the movement of the base molecules with respect to the nucleotide chain, thermal vibration of the base molecules, the orientation or vibration of the DNA molecules caused by the electric field of the electrode, and the like. Non Patent Literature 1 describes that such distributions are caused. However, it does not specifically disclose how each of bases is identified according to distributions which include overlapping portions.